This invention relates to methods for the cleaning of small containers for medical applications, particularly those with small orifices and with abrupt orifice shoulder areas, to the cleanliness standards necessary for pharmaceutical use with injectable preparations.
Before a container, such as a glass vial, can be used for an injectable pharmaceutical product it must be scrupulously cleaned. The cleaning process is used to free it from particulate contaminants that could, when injected, result in circulatory system obstruction. These particulate contaminants can be introduced into the container during formation, shipment and storage prior to use. Containers in general, used for small volume injectable preparations, e.g., those in the volume range from 1 to 100 milliliters, have a special disability. The small diameter container orifice, combined with small container volume, has been recognized as a limitation on the cleanliness that can be achieved. Balancing health risk versus benefit of the many important small volume injectable drugs, a special, higher contamination allowance in particle contamination standards has been set by the United States Pharmacopeia, (USP 24 official from Jan. 1, 2000) for small volume injectable products.
Particle contamination standards are defined separately for the small volume injectable range (those containers 1-100 ml) in capacity from those in the large volume injectable range (containers greater than 100 ml ranging up to 1 liter in capacity). The contamination standard limits are expressed in two size ranges, determined by the perceived effect on the patient. A major contaminant comprises substantially inert particles of detectably large relative size in an objectionably large number. Two quality limit standards have been, for example, set for the number of particles greater than 10 xcexcm and for the number of particles greater than 25 xcexcm depending on container size:
The effect of container size graded contamination standards is thus most disproportionate for small containers. For instance, a 2 ml container, applying large-volume contamination limits, results in a maximum acceptable count of contaminating particles greater than 10 xcexcm to be 50 particles and the limit for particles greater than 25 xcexcm to be 6 particles. However the acceptable limit, using the small container handicap, is 6000 particles greater for xe2x89xa710 xcexcm and 600 greater for xe2x89xa725 xcexcm. The disproportionate quality standards are the result of a defect in the present art employed in the washing of these small containers according to the following procedure:
The small containers, with neck orifices of 13 to 22 mm, are usually jet washed in an inverted position with washing fluid swirling into and out of the inverted container. This procedure results in some contamination re-attachment under most standard washing conditions. Under such conditions, the end-of-wash drain velocity and time become critical factors in the random occurrence of drainage pools in the neck of the container and the consequent re-attachment of contaminating particles in the neck of the container immediately before the orifice. Larger volume containers however maintain a greater exit flow velocity for sufficient time to effectively minimize the re-deposition effect. Such exit velocity is however physically not possible with the smaller containers.
Accordingly in the smaller containers, the re-attached contaminating particles that remain in the container neck area are re-suspended in the liquid contents of the container as a result of handling and transport. Since these contaminating particles in injectable preparations are hazardous to patient health, containers with re-suspended particles are rejected either during the quality assurance inspection or at the medical use point. Rejects at quality assurance inspection add cost to the product. Rejects at the medical use point are damaging to the market image of the producer. A remedy that has been attempted in present art is the use of alternating the single or multiple wash jet positions with single or multiple filtered air or clean steam jets positions. This procedure results in delays of hundreds of milliseconds between the end of the wash jet and the following air or steam jet. This delay period results in the observed random pooling of the exiting wash fluid and the consequent re-attachment of the washed-down contaminating particles, the very condition being sought to be ameliorated.
It is accordingly an object of the present invention to provide an economical method and device for washing small containers, particularly those with the small orifice range and orifice shoulder design in present use, to prevent pooling and re-deposit of contaminants during washing.
Generally the present invention comprises a method and device for the cleaning of containers, and more specifically small volume containers up to about 100 ml, having a reduced orifice dimension and abruptly designed orifice shoulder regions, i.e., of smaller diameter than the remainder of said container, to prevent redeposit of initially dislodged contaminants thereon. The method of the present invention comprises the step of inverting the container and maintaining a film flow in the wash liquid effluent through the neck and shoulder area. The film flow serves to prevent the re-attachment of contaminating particles dislodged in the washing process. In a preferred embodiment of the present invention elimination of the re-attachment with formation of a flowing film is achieved by the simultaneous use of a cleaning fluid such as water and streams of an inert gas such as air or steam during the washing process. The combination of water and air under a pressure between about 5-30 psi provides a constant film flow as required. A device made in accordance with the present invention comprises inlet means for introduction of combined cleaning fluids such as water and air or clean steam being introduced into a container for the cleaning thereof.
The use of film flow for the effluent wash liquid ensures that particles detached in the wash procedure are maintained within a moving stream of wash fluid until exit from the container. For symmetrical containers with shoulders contoured in the flow direction, equal air and water volumes are adequate. For containers with squared shoulders, and other sharp internal discontinuities, air/water ratios and the delivery pressure employed are determined accordingly to maintain the flowing film in the discontinuities. In any event, pooling of exit water in the shoulder during the drainage must be avoided.
The above and other objects, features and advantages of the present invention will become more evident from the following discussion and drawings in which: